Egypt J Pediatr Allergy Immunol 2008; 6(1): 35-37.

Continuous Medical Education

Pathogenesis of primary tubulointerstitial nephritis

Sawsan Moselhy
Professor of Pediatrics, Ain Shams University
Primary tubulointerstitial nephritis (TIN) is the
term applied to conditions characterized by
tubulointerstitial inflammation and damage with
relative sparing of glomeruli and vessels. Both
acute and chronic forms exist (table 1). In
addition, TIN can be present with primary
glomerular diseases affecting the kidney.1
Although interstitial nephritis can be a primary
cause of renal failure, it usually follows
glomerular injury, which probably initiates
secondary interstitial disease as a consequence of
persistent proteinuria and cytochinuria from leaky
glomeruli.2 TIN may be the final common
pathway to renal failure.3 Regardless of the
etiology, the interstitial changes are characteristic
and
include
macrophage
accumulation,
mononuclear inflammation, proteolysis, and
tubular atrophy with concomitant fibrosis.4
Many forms of tubulointerstitial injury
involve exposure to drugs or other nephrotoxic
agents (table 1). Currently, acute TIN is mainly
drug induced. Non-steroidal anti-inflammatory
drugs (NSAID) are the most frequent cause of
permanent renal insufficiency after acute TIN.5

Pathophysiology
The tubulointerstitial lesions in all forms of TIN
are characterized by predominantly T-cell
lymphocytic infiltrates, suggesting immunemediated mechanisms of renal injury. Such
mechanisms may initiate tubular injury or amplify
damage induced by both immune and non
immune causes.6 Cell mediated immune
mechanisms seem to be more important than
humorally mediated mechanisms in the
pathogenesis of TIN.7
Cell mediated immunity
Cell mediated responses are initiated by T-cell
recognition of relevant antigen presented in the
context of appropriate major histocompatibility
complex (MHC) molecules.8 The cause for
antigen expression is unknown. Tubular epithelial
cells normally do not express costimulatory
molecules such as CD80 and CD86 which likely
limits their ability to present antigens under
physiologic conditions.9

Table 1. Etiology of interstitial nephritis.

Acute tubulointerstitial nephritis
Drugs e.g. penicillins, cephalosporins, erythromycin
derivatives, sulfa drugs, non-steroidal antiinflammatory drugs, diuretics, cimetidine,
cyclosporine
Immunologic diseases ( associated with lupus,
Goodpasture syndrome)
Acute transplant rejection
Infections
Bacterial associated with acute pyelonephritis
Viral (cytomegalovirus, hantavirus, HIV, hepatitis
B, Epstein Barr, adenovirus)
Parasitic (Toxoplasma)
Idiopathic
Chronic tubulointerstitial nephritis
Drugs (analgesics, lithium, cyclosporine, tacrolimus)
Heavy metals ( lead, cadmium, mercury)
Obstructive uropathy, nephrolithiasis, reflux disease
Immunologic diseases
Lupus, Sjgren syndrome, primary
glomerulopathies, sarcoidosis
Vasculitis, antineutrophil cytoplasmic antibody
(ANCA)associated vasculitides, Wegener
granulomatosis
Chronic transplant nephropathy
Infections (as the acute)
Metabolic diseases (e.g. hypercalcemia, cystinosis,
hyperoxaluria)
Genetics (e.g., Alport syndrome, medullary cystic
disease)
Miscellaneous (e.g., Balkan endemic nephropathy,
Chinese herb nephropathy, radiation, neoplasm)
Idiopathic

Modified from Dell and Avner1

Genetic susceptibility may play a factor in antigen
expression and consequent immune response.10
Other mechanisms, such as drugs or infectious
agents, may serve as inciting agents of cellmediated responses targeting the kidney.11 Drug
specific T cells are activated locally and
orchestrate a local inflammation via secretion of
various cytokines. Immunohistochemistry of
kidney biopsies of patients with drug induced IN
revealed cell infiltrations that consisted mostly of

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Moselhy

T cells (CD4+ and/or CD8+). An augmented

presence of IL-5, eosinophils, neutrophils, CD68+
cells and IL-12 was observed.12
Antibody mediated immunity
Antibody mediated TIN is occasionally seen.
Anti-tubular basement membrane (TBM) staining
often occurs as part of anti-glomerular basement
membrane (GBM) disease but at times it appears
to be a primary phenomenon resembling
experimental anti-TBM disease. Anti-TBM
antibodies can be seen at times in association with
drug-induced TIN and in the setting of renal
transplantation due to the presence of foreign
antigens in the transplanted kidney13. Antitubular
basement membrane disease is a form of primary
interstitial nephritis mediated by T cells and alpha
TBM antibodies. In mice and humans, the
nephritogenic immune response is directed to a
glycoprotein (3M-1) found along the proximal
tubule of the kidney.14
Local and extra-renal antigens
Two main categories of antigens can induce
experimental TIN (1) endogenous renal antigens
which can be either non-collagenous components
of TBM or proteins synthesized by tubular cells,
and (2) non-renal antigens.4,15
Mechanisms whereby a drug or (one of its
metabolites) can induce acute interstitial
nephritis (AIN):16
(A) The drug can bind to a normal component of
the TBM and act as hapten.
(B) The drug can mimic an antigen normally
present within the TBM or the interstitium and
induce an immune response that will be directed
against this antigen.
(C) The drug can bind to the TBM or deposit
within the interstitium and act as an implanted
antigen.
(D) The drug can elicit the production of
antibodies and become deposited in the
interstitium as circulating immune complexes.
Circulating immune deposits that settle in the
interstitium can cause TIN. This might be the case
in SLE, and IgA nephropathy.17
Cytokines and amplification of injury
Experimental studies and analysis of renal
biopsies have shown that macrophages,
lymphocytes and activated tubular cells can
produce many cytokines that can induce a
proliferation of fibroblastic cells, and /or increase
the production of extracellular matrix.18,19 For

36

example, inflammatory cells can produce

transforming growth factor- (TGF- ),
interleukin-1 (IL-1), IL-4, and lipid peroxidation
products, which increase the production of
extracellular matrix proteins by fibroblastic cells
in vitro. Similarly, tubular cells can synthesize
TGF-, insulin like growth factor-1 (IGF-1),
endothelin-1 (ET-1), and lipid peroxidation
products. In vivo only three of these molecules
induce fibrotic reactions within the renal
interstitium: TGF-, ET-1, and platelet derived
growth factor-BB (PDGF-BB).16
Fibrogenesis and atrophy
Interstitial fibrosis is the final common pathway
for a variety of glomerular and tubular disorders,
particularly when associated with massive
glomerular proteinuria or the presence of
inflammatory cells in the tubulointerstitial
compartment.
Tubulointerstitial
scars
are
primarily composed of collagen types 1 and 3,
fibronectin, and tenascin. Early in the
development of a scar, the fibrotic tissue may
contain monocytes, tubular cells, and fibroblasts.
The source of fibroblasts in the tubulointerstitium
is yet unknown. There are several lines of
evidence suggesting that they may arise from
transformation of resident cells like the tubular
epithelium. This mechanism is called epithelial
mesenchymal transformation (EMT). The
transformation is probably activated by immunemediated mechanisms and various cytokines.
EMT plays an important role in organ remodeling
during fibrogenesis. In the kidney, EMT can be
induced efficiently in cultured proximal tubular
epithelium by incubation of TGF-1 and
epidermal growth factor (EGF). Moreover,
fiboblast growth factor-2 (FGF-2) makes an
important contribution to the mechanisms of EMT
by stimulating microenvironmental proteases
essential for disaggregation of organ-based
epithelial
units.
Tubular
epithelial
to
myofibroblast transition is an orchestrated, highly
regulated process involving four key steps
including: 1) loss of epithelial cell adhesion, 2) de
novo -smooth muscle actin expression and actin
reorganization, 3) disruption of tubular basement
membrane, and 4) enhanced cell migration and
invasion.20-26

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Continuous Medical Education

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